The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, that ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features and repair have been the matter of extensive research and more recently this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use μs-range molecular dynamics simulations and machine learning-based post-analysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple lesions site with a mismatch in 5’ or 3’. We delineate the stiffening of the DNA-protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5’ mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.

中文翻译：

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与成簇病变诱导的人糖基化酶 OGG1 对 8-oxoG 识别障碍相关的分子机制

8-oxo-7,8-dihydroguanine，称为 8-oxoG，是一种高度诱变的 DNA 损伤，如果它逃脱 DNA 损伤反应，就会引起错配的出现。hOGG1 糖基化酶对其结构特征的特异性识别是碱基切除修复途径的第一步，通过防止突变的出现来确保基因组的完整性。8-oxoG 的形成、结构特征和修复一直是广泛研究的问题，最近这一活跃的研究领域扩展到更复杂的 8-oxoG 集群病变案例。事实上，在 1 或 2 个螺旋圈内出现第二个损伤会显着影响糖基化酶对 8-oxoG 的修复产量。在这项工作中，我们使用μs 范围分子动力学模拟和基于机器学习的后分析，以探索与 hOGG1 识别 8-oxoG 相关的分子机制，当嵌入在 5' 或 3' 不匹配的多个病变部位时。我们描述了存在错配时 DNA-蛋白质相互作用的加强，并通过描述添加相邻病变后 8-oxoG 结构特征的扰动来合理化 5' 错配报告的低得多的修复产量。